Most autoimmune diseases affect more females than males. Multiple sclerosis (MS) is a putative autoimmune demyelinating disease of the central nervous system (CNS) characterized in the initial stages by inflammation, in the later stages by neurodegeneration, and has a female bias. This increased susceptibility of females is also present in the mouse model of MS, experimental autoimmune encephalitomyelitis (EAE). While MS occurs in females more frequently and with more robust immune response, MS in men is more progressive (2). Thus, we wonder if there could be opposing sex-related factors in females that impart more robust immune responses but more resilience regarding the CNS response to injury. Sex-related factors underlying sex differences in autoimmune diseases could present a therapeutic target for MS patients. All sex differences ultimately arise from sex chromosomes, either directly from sex-linked transcriptional products or secondarily from sex hormones produced after the differentiation of female- or male-specific reproductive tissues. Our laboratory previously focused on generation of immune responses in EAE and showed that the transfer of PLP 139-151 sensitized lymph node cells with XX sex chromosome complement leads to greater disease severity than cells with XY- complement. These studies used a transgenic mouse model known as the four core genotypes (4CG) in which the Sry gene, which encodes for testicular development, has been deleted from the Y chromosome. This result in XX and XY- ovary-bearing females, where Y- denotes that the Sry gene was deleted and other Y genes remain. In addition, the Sry gene can be added back in an autosomal location resulting in XX Sry and XY- Sry mice which are testes bearing (see review (3)). The 4CG model makes it possible to compare between XX and XY- sex chromosomes on the same hormonal background. While EAE studies in 4CG mice showed a role of sex chromosomes in immune responses, they do not address potential effects mediated by sex chromosomes in the CNS. Irradiation bone marrow chimera is a widely used tool in basic immunology to manipulate the immune system independently from other tissues. I propose that there are sex chromosome effects in the CNS that are independent of effects in the immune system during EAE. Specifically, X chromosome genes may exert a protective effect in the CNS in response to injury. In this proposal, I will test my hypothesis by combining bone marrow chimera and EAE studies in the 4CG females and XY*x mice. The XY*x genotype are females that essentially have 1 X chromosome (1X) and 0 Y chromosome (0Y), and thus can be used to compare with XX (2X, 0Y) and XY- (1X, 1Y) mice for effects of X vs. Y dosage during EAE. These studies will examine the interplay between sex chromosomes, the immune system, and the CNS in an autoimmune demyelinating disease and provide insight into the extent to which sex differences in autoimmune diseases are regulated by sex chromosomes.